Familial Dysautonomia (FD, Riley-Day Syndrome, Hereditary Sensory and Autonomic Neuropathy Type III) [OMIM 223900] is an autosomal recessive disorder present in 1 in 3,600 live births in the Ashkenazi Jewish population. This debilitating disorder is due to the poor development, survival, and progressive degeneration of the sensory and autonomic nervous system (Axelrod et al., 1974). FD was first described in 1949 based on five children who presented with defective lacrimation, excessive sweating, skin blotching, and hypertension (Riley et al., 1949). The following cardinal criteria have evolved for diagnosis of FD: absence of fungiform papillae on the tongue, absence of flare after injection of intradermal histamine, decreased or absent deep tendon reflexes, absence of overflow emotional tears, and Ashkenazi Jewish descent (Axelrod and Pearson, 1984, Axelrod 1984).
The loss of neuronal function in FD has many repercussions, with patients displaying gastrointestinal dysfunction, abnormal respiratory responses to hypoxic and hypercarbic states, scoliosis, gastroesophageal reflux, vomiting crises, lack of overflow tears, inappropriate sweating, and postural hypotension (Riley et al. 1949; Axelrod et al. 1974, Axelrod 1996). Despite recent advances in the management of FD, the disorder is inevitably fatal with only 50% of patients reaching 30 years of age. The clinical features of FD are due to a genetic defect that causes a striking, progressive depletion of unmyelinated sensory and autonomic neurons (Pearson and Pytel 1978a; Pearson and Pytel 1978b; Pearson et al. 1978; Axelrod 1995). This neuronal deficiency begins during development, as extensive pathology is evident even in the youngest subjects. Fetal development and postnatal maintenance of dorsal root ganglion (DRG) neurons is abnormal, significantly decreasing their numbers and resulting in DRG of grossly reduced size. Slow progressive degeneration is evidenced by continued neuronal depletion with increasing age. In the autonomic nervous system, superior cervical sympathetic ganglia are also reduced in size due to a severe decrease in the neuronal population.
Previously, the FD gene, DYS, was mapped to an 11-cM region of chromosome 9q31 (Blumenfeld et al. 1993) which was then narrowed by haplotype analysis to <0.5 cM or 471 kb (Blumenfeld et al. 1999). There is a single major haplotype that accounts for >99.5% of all FD chromosomes in the Ashkenazi Jewish (AJ) population. The recent identification of several single nucleotide polymorphisms (SNPs) in the candidate interval has allowed for further reduction of the candidate region to 177 kb by revealing a common core haplotype shared by the major and one previously described minor haplotype (Blumenfeld et al. 1999).